Discovery, Structural Refinement and Therapeutic Potential of Farnesoid X Receptor Activators
Farnesoid X receptor acts as bile acid sensing transcription factor and has been identified as valuable molecular drug target to treat severe liver disorders, such as non-alcoholic steatohepatitis (NASH). Preclinical and clinical data indicate anti-fibrotic effects obtained with FXR activation that also appear promising for other fibrotic diseases beyond NASH. Strong efforts in FXR ligand discovery have yielded potent steroidal and non-steroidal FXR activators, some of which have been studied in clinical trials. While the structure–activity relationship of some FXR agonist frameworks have been studied extensively, the structural diversity of potent FXR activator chemotypes is still limited to a handful of well-studied compound classes. Together with safety concerns related to full therapeutic activation of FXR, this indicates the need for novel innovative FXR ligands with selective modulatory properties. This chapter evaluates FXR's value as drug target with emphasis on fibrotic diseases, analyses FXR ligand recognition and requirements and focuses on the discovery and structural refinement of leading FXR activator chemotypes.